A Brazil-Ireland Platform for the Development of Metal-Based Therapeutics Professor Michael Devereux Dublin Institute of Technology
PURPOSE OF THE COLLABORATION A interdisciplinary team of chemists and biologists with diverse and complementary expertise undertaking a comprehensive chemical and biological research programme aimed at developing novel metal- based therapeutic agents with potential beneficial effects for: i) Treatment of a range of serious microbial pathogenic diseases including bacterial, protozoal and fungal infections, some of which present specific public health challenges in Brazil (i) Age-related diseases such as Parkinson’s and Cancer.
THE PRINCIPAL AND KEY COLLABORATORS Malachy McCann André L.S. Santos Kevin Kavanagh Marta H. Branquinha Denise Rooney Marcos D. Pereira Livia Viganor Cátia Lacerda Sodré Michael Devereux Orla Howe Pauraic McCarron Mary McNamara Ana Paula Ferreira Nunes Lucimar F. Kneipp Bernie Creaven Mariangela Ziccardi de Camargo Salles Fernanda Lopes Fonseca Andrew Kellett Adolfo Horn Jr. Sarah S. Ferreira Note: The collaboration has also involved approximately 25 postgraduate and postdoctoral researchers
ESTABLISHMENT OF THE COLLABORATION 2005 : Initial contact made by André Santos (UFRJ) – interested in published antimicrobial activity profiles for metal-phenanthroline complexes (MU and DIT). 2012 : First joint publications (UFRJ, MU, DIT, DCU) – with no face- to-face engagement. 2013 – 2016 : Face-to-face meetings in Rio de Janeiro and Dublin ( SFI-ISCA and FAPERJ ). 2014 : Established the Metal-Based Therapeutics Working Group as part of the Research Brazil-Ireland (RBI) initiative. 2015 : 1 st Brazil-Ireland Science Week held in Dublin Castle – significant face-to-face opportunity (six Brazilian collaborators attended). 2015 – present: two-way student and staff mobility (Supported by Science Without borders, FAPERJ, SFI-ISCA, HEA GOI International Education Scholarships, DIT).
Collaboration Outputs Publications, Conference presentations and Seminars 2010-2018 25 20 15 10 5 0 2010 2011 2012 2013 2014 2015 2016 2017 2018 1 st face-to-face meetings
THERAPEUTIC FOCUS Drug resistance is a common Present specific public health challenges in Brazil Require cheap effective BACTERIAL PARASITIC FUNGAL alternatives to expensive Pseudomonas aeruginosa Eg. Leishmania spp. Candida spp. state-of-the-art drugs Klebsiela pneumonia Scedosporium spp. Acinetobacter baumannii Fonsecaea pedrosoi Mycobacterium tuberculosis Phialophora verrucosa Exophiala dermatitidis Cladophialophora carrionii ANTI- NEURODEGENERATIVE ANTICANCER ACTIVITY ACTIVITY
THE CHEMISTRY - METAL-PHENANTHROLINE COMPLEXES Lead: M. Devereux (DIT) and M. McCann (MU) Cheap & easily Active against a synthesised in range of high yield. bacterial and fungal strains. Structural variation easily achieved . Exhibit biomimetic The metal activity (SOD, centre easily CAT, nuclease, varied – Cu, etc..). Mn, Ag. Display Stable with antioxidant & variable cytotoxic solubility capabilities. and lipophilicity. M. Devereux and McCann et al in: Medicinal Chemistry Communications , 2011, 2, 579-584 Journal of Medicinal Chemistry, 2012, 55 , 1957-1968. Dalton Transactions , 2011, 40, 1024, 1024 – 1027. Current Medicinal Chemistry, 2015, 22, 2199-2224. Free Radical Biology and Medicine , 2012, 53 , 564-576. Journal of Inorganic Biochemistry , 2016, 159, 120-132. Dalton Transactions . 2012, 41 (21), 6516 - 6527 Current Topics in Medicinal Chemistry , 2017, 17(11), 1280-1302. International journal of clinical pharmacology and Current Medicinal Chemistry , 2018, 25, 1-14. therapeutics , 2012, 50(1), 79-81
Example 1: S tudies on Phialophora verrucosa with [Ag(phendione) 2 ] + Lead: Lucimar Kneipp (Fiocruz) Phialophora verrucosa is an etiological agent for the chronic subcutaneous disease Chromoblastomycosis - Characterised by polymorphic skin lesions – can lead to skin cancer Affects mainly farm workers Resistance to state-of-the-art antifungals is now a major problem - Expensive to treat In vitro activity of [Ag(phendione) 2 ] + • Inhibits the cellular growth (MIC 100 = 4.0 µM) • Reduces ergosterol in the cell membrane • Reduces metallopeptidase activity • Induces morphological changes • Active towards biofilm • Reduces the viability of the fungus after interaction with human macrophages (THP-1) In vivo activity of [Ag(phendione) 2 ] + Promotes a protective effect in Galleria mellonella (waxmoth) larvae infected with Phialophora verrucosa . 1,10-phenanthroline-5,6-dione compounds are effective in blocking crucial physiological events of Phialophora verrucosa. M. Q. Granato, D. S. Gonçalves, S. H. Seabra, M. McCann, M. Devereux, M. C.V. Pessolani, A. L.S. Santos, L. F. Kneipp, Frontiers in Microbiology , 2017, 8, article 76. In vitro and in vivo studies of 1,10-phenanthroline-5,6-dione – based compounds on Phialophora verrucosa conidia cells. Granato, M.Q., Pereira, M., Pessolani, M.C.V., McCann, M., Devereux, M., Santos, A.L.S., Kneipp, L.F, in preparation.
Example 2:S tudies on the Leishmania braziliensis parasite with [Ag(phendione) 2 ] + and [Cu(phendione) 3 ] 2+ Lead: André Santos (UFRJ) Leishmania braziliensis parasite carried by Sand Fly Leishmaniasis - endemic in Brazil - clinical manifestations: cutaneous, mucocutaneous and visceral forms - disfiguring with considerable morbidity and mortality Current treatment involves The promastigote is the infective form antimony-based drugs such as of the parasite Glucantime – but resistance now a major problem Resistance Glucantime In vitro - [Cu(phendione) 3 ] 2+ superior to [Ag(phendione) 2 ] + (The mechanism of action has been extensively studied) Unpublished results
In vivo activity - L. braziliensis -infected hamsters were treated with [Ag(phendione) 2 ] + and [Cu(phendione) 3 ] 2+ - Compounds intraperitoneally injected once a day for eight consecutive weeks. - The lesion size on the foot was measured weekly over 8 weeks 0 .4 C ontrol D M S O G lucantim e Results Phenanthroline Phendio C u(phendio) 2 0 .3 • Significant reduction in the size of the Le sio n S ize (m m ) A g(phendio) 2 lesions compared to control ( Cu complex is best ) 0 .2 • The silver and copper compounds were 0 .1 well tolerated with no mortality observed during the period of treatment. 0 .0 0 1 2 3 4 5 6 7 8 9 W e e k s a fte r in fe c tio n In vivo - [Cu(phendione) 3 ] 2+ displayed comparable activity to that of the clinical drug Glucantime Unpublished results
Example 3: Antioxidant and potential anti-neurodegenerative capability of [Mn 2 (oda)(phen) 4 (H 2 O) 2 ] 2+ Lead: Marcos Pereira (UFRJ) Solid-state structure of Mn 4 Double salt [Mn 2 (oda)(phen) 4 (H 2 O) 2 ][Mn 2 (oda)(phen) 4 (oda) 2 ].4H 2 O Aqueous solution 2 [Mn 2 (oda)(phen) 4 (H 2 O) 2 ] 2+ + 2 oda 2- (where odaH 2 = octanedioic acid; phen = 1,10-phenanthroline) Antioxidant Activity of [Mn 2 (oda)(phen) 4 (H 2 O) 2 ] 2+ - displays potent acellular superoxide dismutase (SOD) and catalase (CAT) activity. - protects S. cerevisiae and G. mellonella from H 2 O 2 -induced oxidative stress; S. cerevisiae G. mellonella 100 * * * * * 90 80 70 Survival (%) 60 50 40 30 20 10 0 H 2 O 2 2mM 0,1 µ M 0,5 µ M 1 µ M 10 µ M 25 µ M Evaluation of antioxidant activity of a Mn 2+ coordination compound and its potential therapeutic use against alpha-synuclein aggregation. T. P. Ribeiro, J. Freitas, S. Frases, A. S. Pinheiro, M. McCann, M. Devereux, T. F. Outeiro and M. D. Pereira, in preparation,
Anti-neurodegenerative capability • α -Synuclein is a pre-synaptic protein, highly expressed in the central nervous system. • Its oligomerisation, aggregation and accumulation leads to the formation of Lewy Bodies , the pathological hallmark of Parkinson’s Disease. • Lewy bodies develop in nerve cells in regions of brain involved in motor control [Mn 2 (oda)(phen) 4 (H 2 O) 2 ] 2+ : • reduces α -Synuclein toxicities in a yeast model of Parkinson’s Disease . • mitigates oligomerization and aggregation of α -Synuclein in mammalian neuroglioma H4 cells. • NMR spectroscopy indicates that it binds to the C-terminal of α -Synuclein through interactions with Aspartic acid residues which are critical components for oligomerisation. [Mn 2 (oda)(phen) 4 (H 2 O) 2 ] 2+ offers potential as a prototype for Parkinson’s Disease therapeutics Evaluation of antioxidant activity of a Mn 2+ coordination compound and its potential therapeutic use against alpha-synuclein aggregation. T. P. Ribeiro, J. Freitas, S. Frases, A. S. Pinheiro, M. McCann, M. Devereux, T. F. Outeiro and M. D. Pereira, in preparation,
Deciphering the mechanisms of antimicrobial action of 1,10-phenantroline- 5,6-dione- based metallocompounds on Pseudomonas aeruginosa Anna Clara M. Galdino, Lívia, V. Silva, Malachy McCann, Michael Devereux, Marta H. Branquinha, André L.S. Santos
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